The insulin-like growth factors (IGFs) are critical for both pre-natal and post-natal development. In rodents the IGF-I gene is expressed in virtually all tissues and plays a role in the specific functions of these tissues in adult animals. Gene knock-out experiments using homologous recombination techniques have demonstrated that the lack of the IGF-I gene results in peri-natal mortality and growth retardation in the surviving offspring. In addition, these animals are infertile. However, the fundamental question as to whether the circulating (endocrine) form of IGF-I is critical for growth and other tissue functions, or whether the local (paracrine) production of IGF-I is important, remains to be established. We have set out to answer these fundamental questions by using the homologous reacombination technique that utilizes the unique Cre recombinase/loxP system. This system allows for tissue-specific deletion of a gene. Lox/P sequences are introduced into the introns encompassing a critical exon (in this case the IGF-O gene) and these animals are bred to homozygosity. They are mated with animals expressing the Cre recombinase protein that is expressed in a tissue-specific manner (using tissue-specific promoters), and the expression of the Cre recombinase, causes recombination at the lox/P site resulting in removal of the exon and absence of IGF-I production in that tissue. Our first model involved the EIIa-Cre transgenic mice model. These animals express Cre at the preimplantation stages of development. The Cre effect results in a mosaic pattern. Homozygous lox/P mice crossed with the Cre-expressing animals demonstrated up to 80% cleavage of the IGF-I gene on Southern analysis and PCR examination. They demonstrated a parallel diminution in mRNA levels in liver and brain. Interesting, their groath rate post-natally was reduced by only about 25% and the circulating IGF-I levels paralleled the growth rate reduction. Preliminary conclusions from these studies are that the post-natal growth rates in rodents is correlated with circulating IGF-I levels, however, a marked reduction in liver IGF-I gene expression (traditionally considered the endocrine source of circulating IGF-I) may not be the main regulator of this function. Further studies are on-going to settle this question, including the production of a liver-specific (albumin promoter driven) Cre transgenic animal.